An integrated view of anti-inflammatory and antifibrotic targets for the treatment of NASH

Journal of Hepatology, Journal Year: 2023, Volume and Issue: 79(2), P. 552 - 566

Published: April 14, 2023

Language: Английский

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New insights into fibrosis from the ECM degradation perspective: the macrophage-MMP-ECM interaction

Cell & Bioscience, Journal Year: 2022, Volume and Issue: 12(1)

Published: July 27, 2022

Fibrosis is a pathological feature of variety chronic inflammatory diseases that can affect almost all organs, which cause severe consequences and even lead to death. characterized by the excessive accumulation extracellular matrix (ECM) due disruption balance between ECM production degradation. Although overabundance proteins has long been focus studies on fibrosis, another facet problem-impaired degradation ECM-is gaining increasing attention. Matrix metalloproteinase (MMP) tissue inhibitor (TIMP) system main molecular contributing degradation, macrophages are major regulators ECM. However, relationship among macrophages, MMP/TIMP not fully understood in context fibrosis. Here, we discuss detail role played development fibrosis highlight macrophage-MMP-ECM interaction involved fibrogenesis may be potential therapeutic target for

Language: Английский

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Liver Fibrosis Resolution: From Molecular Mechanisms to Therapeutic Opportunities

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(11), P. 9671 - 9671

Published: June 2, 2023

The liver is a critical system for metabolism in human beings, which plays an essential role abundance of physiological processes and vulnerable to endogenous or exogenous injuries. After the damage liver, type aberrant wound healing response known as fibrosis may happen, can result excessive accumulation extracellular matrix (ECM) then cause cirrhosis hepatocellular carcinoma (HCC), seriously endangering health causing great economic burden. However, few effective anti-fibrotic medications are clinically available treat fibrosis. most efficient approach prevention treatment currently eliminate its causes, but this approach’s efficiency too slow, some causes cannot be fully eliminated, worsen. In cases advanced fibrosis, only transplantation. Therefore, new treatments therapeutic agents need explored stop further development early reverse process achieve resolution. Understanding mechanisms that lead necessary find targets drugs. complex regulated by variety cells cytokines, among hepatic stellate (HSCs) cells, their continued activation will progression It has been found inhibiting HSC activation, inducing apoptosis, inactivating activated (aHSCs) thus regression. Hence, review concentrate on how HSCs become during including intercellular interactions related signaling pathways, well targeting pathways resolution Finally, compounds summarized provide more options therapy

Language: Английский

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Matrix metalloproteinases induce extracellular matrix degradation through various pathways to alleviate hepatic fibrosis

Biomedicine & Pharmacotherapy, Journal Year: 2023, Volume and Issue: 161, P. 114472 - 114472

Published: March 2, 2023

Liver fibrosis is the common consequence of various chronic liver injuries and mainly characterized by imbalance between production degradation extracellular matrix, which leads to accumulation interstitial collagen other matrix components. Matrix metalloproteinases (MMPs) their specific inhibitors, that is, tissue inhibitors (TIMPs), play a crucial role in synthesis lysis. Previous vivo vitro studies our laboratory found repressing (ECM) restoring balance MMPs TIMPs can alleviate fibrosis. We conducted review articles published PubMed Science Direct last decade until February 1, 2023, were searched for using these words "MMPs/TIMPs" "Hepatic Fibrosis." Through literature review, this article reviews experimental based on MMPs/TIMPs, summarizes components may exert an anti-liver effect affecting expression or activity attempts clarify mechanism MMPs/TIMPs regulating homeostasis, so as provide support development drugs. MMP-TIMP-ECM interaction result better understanding pathogenesis progression hepatic from different angle, targeting be promising therapeutic strategy Additionally, we summarized analyzed drugs have been reduce changing ratio including medicine natural products.

Language: Английский

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Macrophage in liver Fibrosis: Identities and mechanisms

International Immunopharmacology, Journal Year: 2023, Volume and Issue: 120, P. 110357 - 110357

Published: May 22, 2023

Liver fibrosis is a chronic disease characterized by the deposition of extracellular matrix and continuous loss tissues that perform liver functions. Macrophages are crucial modulators innate immunity play important roles in fibrogenesis. comprise heterogeneous subpopulations exhibit different cellular Understanding identity function these cells essential for understanding mechanisms According to definitions, macrophages divided into M1/M2 or monocyte-derived macrophages/Kupffer cells. Classic phenotyping corresponds pro- anti-inflammatory effects, and, therefore, influences degree later phases. In contrast, origin closely associated with their replenishment activation during fibrosis. These two classifications depict dynamics liver-infiltrating macrophages. However, neither description properly elucidates positive negative role Critical tissue mediating include hepatic stellate fibroblasts, being particular interest because close association molecular biological descriptions inconsistent between mice humans, warranting further investigations. fibrosis, can secrete various pro-fibrotic cytokines, such as TGF-β, Galectin-3 interleukins (ILs), fibrosis-inhibiting IL10. secretions may be specific spatiotemporal characteristics Furthermore, dissipation, degrade secreting metalloproteinases (MMPs). Notably, using therapeutic targets has been explored. The current approaches categorized follows: treatment macrophage-related molecules macrophage infusion therapy. Although there have limited studies, shown reliable potential treatment. this review, we focu on relationship progression regression

Language: Английский

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The role of matrix metalloproteinase 9 in fibrosis diseases and its molecular mechanisms

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 171, P. 116116 - 116116

Published: Jan. 5, 2024

Fibrosis is a process of tissue repair that results in the slow creation scar to replace healthy and can affect any or organ. Its primary feature massive deposition extracellular matrix (mainly collagen), eventually leading dysfunction organ failure. The progression fibrotic diseases has put significant strain on global health economy, as result, there an urgent need find some new therapies. Previous studies have identified inflammation, oxidative stress, cytokines, remodeling play crucial role are essential avenues for treating diseases. Among them, metalloproteinases (MMPs) considered main targets treatment since they driver involved ECM degradation, inhibitors (TIMPs) natural endogenous MMPs. Through previous studies, we found MMP-9 target However, it worth noting plays bidirectional regulatory different stages same disease. Previously inhibitors, such pirfenidone nintedanib, suffer from rather pronounced side effects, therefore, investigate drugs. In this review, explore mechanism action signaling pathways tissues organs, hoping provide ideas developing safer more effective biologics.

Language: Английский

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Liver Fibrosis: From Basic Science towards Clinical Progress, Focusing on the Central Role of Hepatic Stellate Cells

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(14), P. 7873 - 7873

Published: July 18, 2024

The burden of chronic liver disease is globally increasing at an alarming rate. Chronic injury leads to inflammation and fibrosis (LF) as critical determinants long-term outcomes such cirrhosis, cancer, mortality. LF a wound-healing process characterized by excessive deposition extracellular matrix (ECM) proteins due the activation hepatic stellate cells (HSCs). In healthy liver, quiescent HSCs metabolize store retinoids. Upon fibrogenic activation, transdifferentiate into myofibroblasts; lose their vitamin A; upregulate α-smooth muscle actin; produce proinflammatory soluble mediators, collagens, inhibitors ECM degradation. Activated are main effector during fibrogenesis. addition, accumulation profibrogenic macrophages in response hepatocyte death play role initiation HSC survival. source myofibroblasts resident HSCs. migrate site active fibrogenesis initiate formation fibrous scar. Single-cell technologies revealed that highly homogenous, while activated HSCs/myofibroblasts much more heterogeneous. complex results from various hepatocellular inflammatory signals related intrahepatic pathways or extrahepatic mediators. Inflammatory processes modulate activating and, turn, drive immune mechanisms via cytokines chemokines. Increasing evidence also suggests cellular stress responses contribute Recent data demonstrated can revert even advanced stages cirrhosis if underlying cause eliminated, which inhibits cells. However, despite numerous clinical studies on plausible drug candidates, approved antifibrotic therapy still remains elusive. This state-of-the-art review presents molecular involved its resolution, well comprehensively discusses drivers linking LF.

Language: Английский

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GP73-mediated secretion of PKM2 and GP73 promotes angiogenesis and M2-like macrophage polarization in hepatocellular carcinoma

Cell Death and Disease, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 5, 2025

Abstract Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. Abnormally high expression Golgi protein 73 (GP73) and pyruvate kinase M2 (PKM2) intimately associated with HCC progression. However, as secreted proteins, role their extracellular secretions in progression remains unclear. Here, we demonstrated that GP73 was positively correlated PKM2. interacted PKM2 to promote SUMO1 modification PKM2, which turn enhanced interaction This process continuously promoted transfer from cytoplasm membrane cells, finally secretion. Extracellular synergistically angiogenesis polarization M2-type macrophages, thereby leading sorafenib resistance HCC. Sorafenib combined shikonin, a specific inhibitor has strong anti-tumor effect. study reveals enhancing secretion promoting progression, providing theoretical basis drug targets for therapy.

Language: Английский

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Hepatoprotective Effect of Kaempferol: A Review of the Dietary Sources, Bioavailability, Mechanisms of Action, and Safety

Advances in Pharmacological and Pharmaceutical Sciences, Journal Year: 2023, Volume and Issue: 2023, P. 1 - 16

Published: Feb. 27, 2023

The liver is the body’s most critical organ that performs vital functions. Hepatic disorders can affect physiological and biochemical functions of body. disorder a condition describes damage to cells, tissues, structures, liver, which cause fibrosis ultimately result in cirrhosis. These diseases include hepatitis, ALD, NAFLD, fibrosis, cirrhosis, hepatic failure, HCC. are caused by cell membrane rupture, immune response, altered drug metabolism, accumulation reactive oxygen species, lipid peroxidation, death. Despite breakthrough modern medicine, there no effective stimulating function, offering complete protection, aiding regeneration. Furthermore, some drugs create adverse side effects, natural medicines carefully selected as new therapeutic strategies for managing disease. Kaempferol polyphenol contained many vegetables, fruits, herbal remedies. We use it manage various such diabetes, cardiovascular disorders, cancers. potent antioxidant has anti-inflammatory therefore possesses hepatoprotective properties. previous research studied effect kaempferol hepatotoxicity protocols, including acetaminophen (APAP)-induced hepatotoxicity, CCl4, HCC, lipopolysaccharide (LPS)-induced acute injury. Therefore, this report aims provide recent brief overview literature concerning its possible molecular mechanism action. It also provides on kaempferol’s chemical structure, source, bioavailability, safety.

Language: Английский

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YAP/TAZ: Molecular pathway and disease therapy

MedComm, Journal Year: 2023, Volume and Issue: 4(4)

Published: Aug. 1, 2023

The Yes-associated protein and its transcriptional coactivator with PDZ-binding motif (YAP/TAZ) are two homologous coactivators that lie at the center of a key regulatory network Hippo, Wnt, GPCR, estrogen, mechanical, metabolism signaling. YAP/TAZ influences expressions downstream genes proteins as well enzyme activity in metabolic cycles, cell proliferation, inflammatory factor expression, transdifferentiation fibroblasts into myofibroblasts. can also be regulated through epigenetic regulation posttranslational modifications. Consequently, function these mechanisms implicates pathogenesis metabolism-related diseases, atherosclerosis, fibrosis, delicate equilibrium between cancer progression organ regeneration. As such, there arises pressing need for thorough investigation clinical settings. In this paper, we aim to elucidate signaling pathways regulate explore YAP/TAZ-induce diseases their potential therapeutic interventions. Furthermore, summarize current studies investigating treatments targeting YAP/TAZ. We address limitations existing research on propose future directions research. conclusion, review aims provide fresh insights mediated by identify targets present innovative solutions overcome challenges associated

Language: Английский

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